Theoretical review
Dopamine and the spinal cord in restless legs syndrome: Does spinal cord physiology reveal a basis for augmentation?

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Summary

The pathophysiology of restless legs syndrome (RLS) is incompletely understood. l-DOPA, as the precursor of dopamine, as well as dopamine agonists, plays an essential role in the treatment of RLS leading to the assumption of a key role of dopamine function in the pathophysiology of RLS. Periodic limb movements in sleep are a key feature of RLS. They are generated in the spinal cord. Here we review RLS phenomenology on the basis of known dopaminergic influence on spinal control, which has been studied a great deal in recent decades in animals. In particular, we propose that the differential effects of l-DOPA and opioids on early and late flexor reflexes may be linked to the phenomenon of augmentation.

Introduction

Restless legs syndrome (RLS) is associated with an urge to move the legs, usually accompanied by uncomfortable or unpleasant sensations in the legs, often during periods of rest or inactivity such as lying or sitting. Furthermore, partial or total relief through movement such as walking, bending, stretching, etc. at least for as long as the activity continues, belongs to the diagnostic criteria, as does a worsening of these symptoms in the evening or at night. Further supportive criteria are a positive response to dopaminergic treatment and the occurrence of periodic limb movements (PLM) during sleep or wakefulness (overview in1).

The pathophysiology of RLS is probably heterogeneous and at present unresolved.2 In view of the excellent responses to treatment with dopaminergic agents, it is highly likely that both dopamine (DA) and DA agonists are involved.

The spinal cord provides the primary input stage for sensory afferents and the final output stage for periodic limb movement (PLMs). Already at this stage it is possible, in principle, to reduce sensory complaints by active movements, one of the key features of RLS symptomatology. It might be said that the primary necessary condition for a successful correlation with anatomy and physiology is the cessation of RLS symptoms with movement and, vice versa, the dominance of symptoms in periods of motor rest. The focus on the spinal cord in RLS is furthermore warranted in view of the polysomnographical findings of patients with complete transection of the spinal cord, whose involuntary leg movements were identical to sleep-related periodic leg movements (PLMs).3 In another study, this was confirmed in three patients with a spinal cord lesion. Here symptoms resolved after surgical treatment of a schwannoma in one patient.4 8.7% of patients undergoing spinal cord anaesthesia developed first-time RLS.5 Obviously, the spinal cord, deprived of supraspinal influences, is able to generate the rhythm of PLM.

The bulk of animal studies of dopaminergic influence on spinal cord functions have been performed some decades ago, mainly by the Lundberg group, with the interest in this research declining somewhat at the end of the last century. Very recently, modern techniques have rekindled interest in this subject. Two studies involving dopamine D(3) receptor knockout mice (D3KO)6, 7 tried to explain how impaired D3 activity could contribute to this sleep disorder. Here, we review anatomical and physiological data most likely playing a role in PLM generation in the spinal cord and the involvement of the dopaminergic system against the background of the symptomatology of RLS.

Section snippets

Spinal anatomy

Incoming sensory afferents and the motoneurone system are interconnected by the spinal interneuronal system, which is responsible for the generation of simple reflex movements as well as complex motor patterns ranging from tonic to phasic movements and from a co-contraction of antagonistic muscles to coordinated locomotor activity (for a review see 8). The activity of these interneurones in general as well as the activity of spinal nociceptive neurones in the dorsal horn is modulated by

State dependent modulation and PLM generation

The so-called state-dependent modulation of neurotransmission is an important tool to adapt the spinal interneuronal systems quickly to immediate requirements of performing movement in response to the existing conditions. Under normal conditions such as normal sitting, reflexogenic activation is largely downregulated in order to prevent inadequate reflexogenic movements from the continuously activated peripheral receptors. In this downregulated situation, the activity of individual receptor

Spinal excitability, flexor reflex afferents and PLM termination

In the neurological examination, tendon reflexes and the Babinski sign are normal in RLS patients, in contrast to findings in patients with spasticity. Normal tendon reflex excitability has been confirmed in quantitative studies looking at the ratio between the amplitude of the H–reflex and the direct electrical response (H/M ratio) when testing the excitability of the motor neurone pool by H-reflex stimulation.15, 16 Also since H-reflex thresholds in PLMD patients were similar to those in

Dopamine in the spinal cord

The spinal cord itself is virtually devoid of dopaminergic cell bodies. The major source of the spinal dopaminergic projection into the dorsal horn and intermediolateral tract is area A11.22 At first glance, one would expect a lack of l-DOPA efficacy after spinal cord transection or in human patients.3, 23 However, and most surprisingly, DA is even efficient in the spinal cord after complete transection,24 probably due to DA synthesis in the absence of monoaminergic nerves.25 An alternative way

Dopamine effects on the afferent site

Since no RLS animal model is readily available, most data on DA and the afferent site of the spinal cord have been obtained in the course of pain studies. DA may ameliorate chronic pain. In rats, intrathecal administration of the DA agonist apomorphine produced an analgesia, which was antagonized by the prior intrathecal administration of a DA receptor antagonist but not by the administration of α2, serotonin, or opiate antagonists.30 In addition to intrinsic dopaminergic stimulation, it has

Dopamine effects on the efferent and reflex site

The intricate function of the dopaminergic system in spinal motor control becomes evident when l-DOPA is applied in different dosages. Within a medium range of spinal DA concentration in the spinalized cat, locomotor activity (fictive locomotion in the paralyzed animal) can be induced. During fictive locomotion, motoneurones may develop a bi-stable firing characteristic caused by membrane potential switching between two levels and induced by l-DOPA. This does not contradict the surmise that DA

Neuronal hierarchy of segmental dopaminergic intervention

Co-contraction of flexors and extensors may be mediated via segmental subpopulations of group II interneurones (Fig. 3A, arrow). l-DOPA may inhibit this co-contraction by its general inhibitory effect on short latency group II pathways, whereby group II-mediated excitation reacts with greater sensitivity to l-DOPA than pathways from non-nociceptive cutaneous and joint afferents.34

Moreover, the transmission on inhibitory FRA pathways is distinctly less depressed by l-DOPA than that on excitatory

Relation to sleep stages

The circadian rhythm in RLS requires information in the spinal cord from most likely hypothalamic centers. Accordingly, suppression of leg movements during REM sleep was not observed in patients with complete transection of spinal cord.3 With progressive sleep stages from light to deep sleep and then to REM sleep phases, PLMs are progressively suppressed when compared to an awake state in bed.48 In this study, REM sleep was characterized by the shorter duration and the lowest frequency of PLM,

Augmentation: a paradoxical L-DOPA-induced, long-latency FRA effect?

In some patients, after once-nightly treatments with carbidopa or l-DOPA51 and also after treatment with other DA agonists,52 a delayed augmentation of the RLS symptoms was observed the following day. This augmentation, which must be regarded as a serious problem of dopaminergic treatment in RLS patients, has hypothetically been interpreted as a kind of rebound or a result of a suppression of the circadian rhythm via the striatal, hypothalamic or spinal dopaminergic system by the higher l-DOPA

Opioids in the spinal cord

The dramatic therapeutic response to opioids in RLS patients warrants the assumption of a central role in pathophysiology. The efficacy of opiates in the relief of the symptoms is possibly partly related to the dopaminergic system.55 However, the sensitivity to opioids does not imply a crucial role of the nociceptive system in the development of RLS. Like l-DOPA, opioids do not need to have a selective antinociceptive effect at the spinal level, but they suppress segmental pathways from all FRA

Acknowledgements

We thank Mrs Christine Crozier for correcting the English text.

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